This invention relates to medical articles that can be placed in contact with a stream of blood or other tissue and which have surfaces that are anti-thrombogenic. It also relates to a process for treating a medical article to impart anti-thrombogenic properties to a surface thereof.
Articles for contact with circulating blood, whether intra-corporeally or during extracorporeal blood circulation, can give rise to coagulation. In particular, plastics materials have been found to be thrombogenic, even in the case of relatively blood-compatible materials such as polytetrafluoroethylene and silicone rubber. In order to minimize trauma in blood circulating in contact with articles having non-biological surfaces, bonding of heparin to such surfaces has been disclosed, the heparin imparting anti-thrombogenic properties.
Bonding of heparin to surfaces was first described by V. I. Gott et. Al., Science, 142, 1297 (1963), the surfaces being graphitized, treated with benzalkonium chloride and then with heparin. Subsequently a simpler surface treatment was developed based on coating the surface e.g. by simple immersion with a thin layer of tridodecylmethyl ammonium heparinate, see V. I. Gott et. al., Ann. Thoracic Surg., 14, 219 (1972) and A. H. Krause et. al, Ann. Thoracic Surg., 14, 123 (1972). According to a data sheet issued by Polysciences Limited of Northampton, England in 1984 the process was used to make shunts for use in artery bypass. Greater stability to washing can be achieved by cross-linking the bonded heparin molecules with dialdehydes, see U.S. Pat. No. 3,810,781 (Eriksson), and an increased level of heparin uptake can be achieved in the case of plastics articles by glow-or corona-treating the surface of the article, see U.S. Pat. No. 4,613,517. The use of so-called xe2x80x9cDuraflo II heparinxe2x80x9d coatings to reduce blood trauma in extracorporeal circuits e.g. of cardiopulmonary bypass machines is disclosed by Li-Chien Hsu, Cardiac Surgery: state of the art reviews-Vol. 7, No. 2, 265 (1993). The effectiveness of so-called xe2x80x9cheparin bonded circuitsxe2x80x9d in reducing the need for blood transfusion during coronary artery bypass surgery is disclosed by G. M. Mahoney et. al., European Journal of Cardio-thoracic Surgery.
Various references disclose the treatment of surfaces with heparin and with a silicone. For example U.S. Pat. No. 4,529,614 (Burns) discloses the coating of microcontainer tubes for use in blood testing with an aqueous solution of heparin and an organopolysiloxane to form a hydrophobic anticoagulant layer. U.S. Pat. No. 5,061,738 (Solomon et al) discloses a medical device such as a probe, cannula or catheter which is rendered both antithrombogenic and lubricious by treatment of a mixture of a quaternary ammonium complex of heparin and a non-curing lubricating silicone which may be a polydialkylsiloxane. U.S. Pat. No. 5,182,317 (Winters et. al.) discloses the production of multi-functional thrombo-resistant coatings for use with biomedical devices and implants. A material is prepared which has a siloxane surface onto which a plurality of amine functional groups is bonded. Either the surface is plasma etched with ammonia gas or a siloxane monomer is plasma polymerized in the presence of ammonia gas. The resulting siloxane surface containing amine groups is reacted with poly(ethylene oxide) chains terminated with functional groups that can react with the amine groups on the siloxane surface. The product is then further reacted with at least two different molecules that are capable of resisting blood material incompatibility reactions. U.S. Pat. No. 5,541,167 discloses a device for removing air bubbles from blood (xe2x80x9cdefoamingxe2x80x9d) before the blood is returned to a patient. Sequential coatings of a quaternary ammonium complex of heparin and of a mixture of a polysiloxane and silicon dioxide are applied.
The present invention provides a polymeric coating that may be applied to an article for surgery, diagnosis or other medical treatment and in which heparin and/or or another negatively charged biologically active molecule is simply and effectively bound to a substrate.
The substrate is treated with a polydimethylsiloxane-based primer which adheres firmly to the surface of the article without the need for pre-treatment (e.g. by plasma discharge or by a coupling agent) and which has exposed cationic sites. The primer forms a thin transparent layer and is not detrimental to the mechanical properties of the device. Simultaneously or subsequently the heparin and/or other negatively charged biologically active molecules are applied to the article. Treatment can be carried out at ambient temperatures. After treatment the article may be washed to remove solvent and un-reacted reagent and dried either with moderate heat insufficient for reduction of the biological activity of the heparin to take place or at ambient temperatures.
In one aspect the invention provides an article having a surface for contact with circulating blood, said surface having a coating of an organopolysiloxane and heparin, wherein the organopolysiloxane is adherent to the surface of the article and has cationic groups that form ionic bonds with anionic groups of the heparin.
In another aspect the invention provides an article having a surface for contact with circulating blood, said surface having a coating of an organopolysiloxane and a biologically active material having anionic groups, wherein the organopolysiloxane is adherent to the surface of the article and has cationic groups that form ionic bonds with anionic groups of the biologically active material. The anionic biologically active molecule may, for example be a diagnostic agent, growth factor, antibody. prostaglandin (which can inhibit thrombus formation and platelet activity) or protein.
In a further aspect, the invention provides a method for forming a coated article as defined above, said method comprising:
contacting said surface with a solution in a volatile organic solvent of an organopolysiloxane and with heparin, the organopolysiloxane being adherent to the surface of the article and having cationic groups that form ionic bonds with the anionic groups of the heparin; and
removing said volatile solvent.
The surface of the article may be coated sequentially with the organopolysiloxane and with heparin, or a complex of the organopolysiloxane and heparin may be formed in solution, after which the solution is contacted with the surface of the article. The process may be applied to the coating of other negatively charged biologically active molecules in addition to or as an alternative to coating with heparin.
Use of the article in the recirculation of blood e.g. as a blood line, oxygenator, heat exchanger, haemodyalyser and/or blood filter is also within the scope of the invention. When heparin treated oxygenators or haemodyalysers are used, the dose of heparin that has to be administered to the patient to enable the treatment to be conducted safely can be reduced.
The article to be rendered bio-compatible may be at least partly of a metal, ceramics or glass. It may also be at least partly of a polymeric material, e.g. polyethylene, polyacrylic, polypropylene, polyvinyl chloride, polyamide, polyurethane, polyvinyl pyrrolidone, polyvinyl alcohol, polystyrene, polysulfone, polytetrafluoroethylene, polyester, silicone rubber, natural rubber, polycarbonate or a hydrogel. The invention is particularly advantageous for the treatment of hollow articles in which the surface for contact with circulating blood is an interior surface, e.g. a cannula or tubing, a blood oxygenator (which may be provided with a reservoir and heat exchanger) or blood filter or haemodyalyser.
The organopolysiloxane is preferably soluble in a lower alcohol, of which 2-propanol is preferred because of its combination of volatility and antiseptic properties. It preferably has trimethylammonium groups linked to a polydimethylsiloxane main chain by grafted polyoxyethylene chains, which preferably include hydroxyl terminated chains, and quaternary ammonium terminated chains. A particular preferred cationic solvent-soluble silicone polymer used is poly-[dimethylsiloxane-co-methyl-(3-hydroxypropyl)siloxane]-graft-poly(ethylene glycol) [3-(trimethylammonio) propyl chloride] ether whose structure is believed to be generally as indicated below:
(CH3)3SiO[(CH3)2SiO]x[(CH3) (RO(CH2 CH2O)y CH2 CH2 CH2)SiO]zOSi(CH3)3xe2x80x83xe2x80x83(1) 
wherein x, y and z represent integers and R, whose value may differ in different units along the chain, represents H or -[CH2 CH2 CH2N+(CH3)3] X wherein X represents chloride or another cation. The material used may typically have a molecular mass of about 4000 and about 4 quaternary ammonium groups per molecule.
The organopolysiloxane may be contacted with the surface of the article whilst it is in solution in an alcohol or aqueous alcohol e.g. 2-propanol. Contact may be at ambient temperatures, and in the case of a hollow article it can simply involve circulation of the solution through the article to permit the organopolysiloxane to form a layer on the surface to be treated. If the ionic complex is not preformed, the heparin or other biologically active material may be applied as an aqueous solution at ambient temperatures, so that the procedures involved are relatively rapid and inexpensive. In the case of an aqueous/alcohol mixture, the alcohol should predominate, a ratio of 1:10 helping to solubilize hydrophilic materials whilst preserving the antiseptic qualities of the alcohol. Where the surface to be treated is one face of a membrane or tube of microporous material (e.g. microporous polypropylene or polysulfone fibers), gas under pressure is preferably supplied to the other face of the membrane or tube to keep the pores open.
The process has been applied successfully to medical devices such as oxygenators, blood filters, and PVC tubing used in glucose monitoring systems, and the coated articles have been successfully tested for biocompatibility. The process has also been applied to haemodyalysers, and both the case and the fibrous membranes of a haemodyalyser have been successfully coated. Our experiment was carried out with a haemodyalyser having microporous polysulfone membranes and a polycarbonate case.
The invention will now be further described, by way of example only with reference to the following examples: